The contribution of the metabolite p -hydroxyamphetamine to the central actions of p -methoxyamphetamine

Kaminskas, Lisa M.; Irvine, Rodney J.; Callaghan, Paul D.; White, Jason M.; Kirkbride, K. Paul

doi:10.1007/s00213-001-0984-z

Cited by 16 publications

(9 citation statements)

References 22 publications

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“…Cytochrome P450-catalyzed hydroxylation of the aromatic ring 4-position is the major pathway of phenylalkylamine metabolism in the rat [Caldwell, 1976]. The product of the hydroxylation of amphetamine, para-hydroxyamphetamine, is an inhibitor of norepinephrine, dopamine, and serotonin uptake [Wenger and Rutledge, 1974;Kaminskas et al, 2002], is twice as potent as amphetamine itself as a sympathomimetic agent [Simpson, 1979[Simpson, , 1980, and is a powerful locomotor stimulant when given intracerebrally [Taylor and Sulser, 1973]. In 3-BMAP and 4-BMAP, there is a bromine atom on the aromatic ring at the 3-or 4-positions, respectively.…”

Section: Discussionmentioning

confidence: 99%

Novel aminopropiophenones as potential antidepressants

Foley

Cozzi

2003

Drug Development Research

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The atypical antidepressant drug bupropion and the psychostimulant drug methcathinone are both members of a chemical class known as aminopropiophenones. Differences in the psychoactive effects of these two drugs result from small variations in their chemical structures, but the relationship between chemical structure and psychoactivity has not been characterized. To investigate how structural modifications to aminopropiophenones affect antidepressant or stimulant activity, we synthesized several analogs of bupropion and methcathinone and tested the new compounds for antidepressant-like or psychostimulant effects. The synthesized compounds are 2-(methylamino)-1-(3-bromophenyl)propan-1-one (3-BMAP), 2-(methylamino)-1-(4-bromophenyl)propan-1-one (4-BMAP), 2-(iso-propylamino)-1-phenylpropan-1-one (i-PAP), and 2-(tert-butylamino)-1-phenylpropan-1-one (t-BAP). Bupropion, methcathinone, desipramine, and the newly-synthesized aminopropiophenones were administered to rats for behavioral testing. We used the Porsolt swim test to assess antidepressant-like activity and a locomotor activity assay to test for psychostimulant effects. All of the compounds displayed antidepressantlike effects in the Porsolt swim test. Some compounds, including bupropion, increased locomotor activity at moderate-to-high doses. A halogenated analog of methcathinone, 4-BMAP, increased swim time but did not stimulate locomotor activity, even at the highest dose tested. The data indicate that phenyl ring substitution or branched alkylamines can shift the psychopharmacological profile of aminopropiophenones from stimulant activity to antidepressant-like activity. Several of the new drugs may be effective antidepressants in humans with fewer stimulant-like side effects compared to bupropion. Drug Dev. Res. 60:252-260, 2003.

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Section: Discussionmentioning

confidence: 99%

Novel aminopropiophenones as potential antidepressants

Foley

Cozzi

2003

Drug Development Research

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“…Produced by the cytochrome P450 detoxification system, POHA is reported to have biological effects of its own (Kaminskas et al, 2002). Following up on the observation reported by Bunzow et al (2001) that a racemic mix of POHA concentration-dependently stimulates cAMP production in cells expressing rTAAR1, the present study examined the ability of each isomer to stimulate cAMP accumulation in each of the three TAAR1-expressing cell lines.…”

Section: Both S-(ϩ)-meth and (R)-(ϫ)-meth Were Full Agonists With S-(mentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Displays Species-Dependent Stereoselectivity for Isomers of Methamphetamine, Amphetamine, and Para-Hydroxyamphetamine

Reese¹,

Bunzow²,

Arttamangkul³

et al. 2007

J Pharmacol Exp Ther

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The synthetic amines methamphetamine (METH), amphetamine (AMPH), and their metabolite para-hydroxyamphetamine (POHA) are chemically and structurally related to the catecholamine neurotransmitters and a small group of endogenous biogenic amines collectively referred to as the trace amines (TAs). Recently, it was reported that METH, AMPH, POHA, and the TAs para-tyramine (TYR) and ␤-phenylethylamine (PEA) stimulate cAMP production in human embryonic kidney (HEK)-293 cells expressing rat trace amine-associated receptor 1 (rTAAR1). The discovery that METH and AMPH activate the rTAAR1 motivated us to study the effect of these drugs on the mouse TAAR1 (mTAAR1) and a human-rat chimera (hrChTAAR1). Furthermore, because S-(ϩ)-isomers of METH and AMPH are reported to be more potent and efficacious in vivo than R-(Ϫ), we determined the enantiomeric selectivity of all three species of TAAR1. In response to METH, AMPH, or POHA exposure, the accumulation of cAMP by HEK-293 cells stably expressing different species of TAAR1 was concentration-and isomer-dependent. EC 50 values for S-(ϩ)-METH were 0.89, 0.92, and 4.44 M for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1, whereas TYR was a full agonist for the rodent TAAR1s but was a partial agonist at h-rChTAAR1. Interestingly, both isomers of METH were full agonists at mTAAR1 and h-rChTAAR1, whereas both were partial agonists at rTAAR1. Taken together, these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs.

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“…To date, the determination of p-methoxyamphetamine in biological samples has been mainly on gas chromatography coupled with several detection methods, such as mass spectrometry (GC-MS) [3,6] and nitrogen phosphorus detector (NPD). [7] Several other analytical methods are described in literature for screening of p-methoxyamphetamine, such as high performance liquid chromatography with fluorescence detection (HPLC-FL) [8] and immunoassays. [9] In the last few years, the liquid chromatography coupled mass spectrometry (LC-MS) has developed rapidly in forensic and clinical applications, as well as in analysis of amphetamines in biological samples.…”

Section: Determination Of P-methoxyamphetamine By Capillary Electrophmentioning

confidence: 99%

Determination of p‐Methoxyamphetamine by Capillary Electrophoresis with Diode Array Detection from Urine and Plasma Samples

Nieddu

Boatto

Sini

et al. 2007

Journal of Liquid Chromatography & Related Technologies

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In recent years, a number of newer designer drugs have entered the illicit drug market. The amphetamine derivatives represent the largest group of designer drugs. This paper describes a method for quantifying p-methoxyamphetamine in human plasma and urine by capillary electrophoresis with a diode array detector. Using an aqueous pH 2.5 phosphate buffer, CE analysis gave peaks with good symmetry and reproducible migration time. Under these experimental conditions, the p-methoxyamphetamine was resolved in 7 min and without interferences from biological matrices. The identification using the migration time was confirmed by UV spectra recorded with a diode array detector DAD (190-350 nm). Prior to CE-DAD analysis, a simple solid phase extraction (SPE) was used for sample cleanup. The main advantages of the present method lie in its simplicity and clean and reliable extraction from plasma and urine. The method was validated according to international guidelines.

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The contribution of the metabolite p -hydroxyamphetamine to the central actions of p -methoxyamphetamine

Abstract: These data indicate that although PHA is more effective than PMA at altering 5HT and dopamine kinetics in vivo, it is unlikely to achieve sufficient brain concentrations to contribute to the central effects of PMA.

Cited by 16 publications

References 22 publications

Novel aminopropiophenones as potential antidepressants

Novel aminopropiophenones as potential antidepressants

Trace Amine-Associated Receptor 1 Displays Species-Dependent Stereoselectivity for Isomers of Methamphetamine, Amphetamine, and Para-Hydroxyamphetamine

Determination of p‐Methoxyamphetamine by Capillary Electrophoresis with Diode Array Detection from Urine and Plasma Samples

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